Ovarian cancer is the fifth leading cause of death from cancer and has the highest mortality rate among the gynecologic malignancies in the United States. According to the American Cancer Society (2002), approximately 23,300 women will be diagnosed with ovarian cancer in the United States and 13,900 will die from the disease. Ovarian tumors are classified by the World Health Organization (WHO) according to their cell type and include, for example, epithelial, germ cell, stromal, and metastatic tumors. Epithelial tumors are the most common type with abnormal masses that typically develop on the surface of ovaries. Stromal and germ cell tumors are typically rare.
Ovarian cancer is often called a “silent killer” due to the lack of noticeable early symptoms. In fact, symptoms specific to ovarian cancer develop only after the disease has spread out of the ovary. Early diagnosis is important because ovarian cancer is very treatable when detected early. For example, if ovarian cancer is detected before it has spread out of the ovary, 95% of women will survive longer than five years; however, if diagnosed in advance stages, only 28% of women will survive longer than five years.
Current approaches to identifying biological markers for diagnosing and treating cancers have mainly focused on proteomics. For example, proteins such as osteopontin, periostin, and HE7 (WFDC2) were identified through proteomics or gene expression analyses and have been suggested to be potential diagnostic markers for ovarian cancer (Kim et al., JAMA, 287:1671-1679 (2002); Hellstrom et al., Cancer Res., 63:3695-3700 (2003); Gillan et al., Cancer Res., 62:5358-5364 (2002)). However, their utility as markers for diagnosing cancer is unknown.
Mucins are expressed and secreted by various epithelial cell types (Van den Steen et al., Crit. Rev. Biochem. Mol. Biol., 33:151-208 (1998)). Epithelial cells are expressed on the outer walls of tissues/organs and are involved in cell-cell or cell-matrix interactions, often acting as the interface between tissues and their environment. Mucins are secreted by normal secretory epithelial cells and have a central role in maintaining homeostasis and the survival of cells (Hanisch, Biol. Chem., 382:143-149 (2001)). Mucins are often characterized as large glycoproteins associated with high levels of glycosylation. Oligosaccharides, primarily O-linked or mucin-type oligosaccharides, make up a large fraction of the mass of mucins (Van den Steen et al., id).
Mucins have long been implicated in the pathogenesis of cancer (Hollingsworth et al., Nat. Rev. Cancer, 4:45-60 (2004)). Most types of adenocarcinomas (i.e., epithelial cell cancers) are often accompanied by high levels of mucin production (Hollingsworth et al., id). For example, mucins such as MUC1 and CA 125 (MUC 16) are elevated in ovarian cancer (Stimpfl et al., Cancer Lett., 145:133-141 (1999)). MUC 1 is found to be commonly associated with breast cancer (Hanisch et al., Eur. J. Biochem., 236:318-327 (1996); Lloyd et al., J. Biol. Chem., 271:33325-33334 (1996); Croce et al., Br. Cancer Res. Treatment, 81:195-207 (2003)). CA 125 (MUC 16) has been commonly used in the clinic as an ovarian cancer marker and has been assessed as a useful biochemical tool for both monitoring and prognostic evaluation of patients with ovarian cancer (Bast et al., N. Engl. J Med., 309:883-887 (1983); Bast et al., J. Clin. Invest., 68:1331-1337 (1981)). However, elevated serum CA 125 levels are found in only 50% of those patients with FIGO (International Federation of Gynecology and Obstetrics scoring system) stage I ovarian cancer (Jacobs et al., Hum. Reprod., 4:1-12 (1989)). In addition, a significant proportion of women with benign conditions such as endometriosis or pelvic inflammatory disease also have raised CA 125 levels (Jacobs et al., id; Mashasi et al., Obstret. Gynecol., 72:328-331 (1988)). Therefore, elevated serum CA 125 levels is not an adequate indicator for detecting early onset ovarian cancer.
The evaluation of the levels of mucins such as CA 125 are complicated by several factors. First, mucins are highly heterogeneous glycoproteins with high molecular weights (e.g., 107 Daltons). Second, antibody methods currently used to detect mucins are imprecise and not quantitative. Third, mucins that are commonly detected, such as CA 125, are not expressed equally by the different tumor types of ovarian cancer.
As such, there is a need in the art for the identification of biological markers for the early detection or diagnosis of adenocarcinomas such as ovarian cancer or breast cancer. The present invention satisfies this and other needs.